PMID- 30550583
OWN - NLM
STAT- MEDLINE
DCOM- 20190506
LR  - 20231005
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 13
IP  - 12
DP  - 2018
TI  - Structural and functional insight into serine hydroxymethyltransferase from 
      Helicobacter pylori.
PG  - e0208850
LID - 10.1371/journal.pone.0208850 [doi]
LID - e0208850
AB  - Serine hydroxymethyltransferase (SHMT), encoded by the glyA gene, is a ubiquitous 
      pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the formation of 
      glycine from serine. The thereby generated 5,10-methylene tetrahydrofolate (MTHF) 
      is a major source of cellular one-carbon units and a key intermediate in 
      thymidylate biosynthesis. While in virtually all eukaryotic and many bacterial 
      systems thymidylate synthase ThyA, SHMT and dihydrofolate reductase (DHFR) are 
      part of the thymidylate/folate cycle, the situation is different in organisms 
      using flavin-dependent thymidylate synthase ThyX. Here the distinct catalytic 
      reaction directly produces tetrahydrofolate (THF) and consequently in most 
      ThyX-containing organisms, DHFR is absent. While the resulting influence on the 
      folate metabolism of ThyX-containing bacteria is not fully understood, the 
      presence of ThyX may provide growth benefits under conditions where the level of 
      reduced folate derivatives is compromised. Interestingly, the third key enzyme 
      implicated in generation of MTHF, serine hydroxymethyltransferase (SHMT), has a 
      universal phylogenetic distribution, but remains understudied in ThyX-containg 
      bacteria. To obtain functional insight into these ThyX-dependent 
      thymidylate/folate cycles, we characterized the predicted SHMT from the 
      ThyX-containing bacterium Helicobacter pylori. Serine hydroxymethyltransferase 
      activity was confirmed by functional genetic complementation of a 
      glyA-inactivated E. coli strain. A H. pylori DeltaglyA strain was obtained, but 
      exhibited markedly slowed growth and had lost the virulence factor CagA. 
      Biochemical and spectroscopic evidence indicated formation of a characteristic 
      enzyme-PLP-glycine-folate complex and revealed unexpectedly weak binding affinity 
      of PLP. The three-dimensional structure of the H. pylori SHMT apoprotein was 
      determined at 2.8A resolution, suggesting a structural basis for the low affinity 
      of the enzyme for its cofactor. Stabilization of the proposed inactive 
      configuration using small molecules has potential to provide a specific way for 
      inhibiting HpSHMT.
FAU - Sodolescu, Andreea
AU  - Sodolescu A
AD  - Laboratory of Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, 
      Universite Paris Saclay, Palaiseau, France.
FAU - Dian, Cyril
AU  - Dian C
AUID- ORCID: 0000-0002-6349-3901
AD  - Institute for Integrative Biology of the Cell, CEA, CNRS, Universite Paris 
      Saclay, Gif-sur-Yvette, France.
FAU - Terradot, Laurent
AU  - Terradot L
AD  - UMR 5086 Molecular Microbiology and Structural Biochemistry, Institut de Biologie 
      et Chimie des Proteines, CNRS, Universite de Lyon, Lyon, France.
FAU - Bouzhir-Sima, Latifa
AU  - Bouzhir-Sima L
AD  - Laboratory of Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, 
      Universite Paris Saclay, Palaiseau, France.
FAU - Lestini, Roxane
AU  - Lestini R
AD  - Laboratory of Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, 
      Universite Paris Saclay, Palaiseau, France.
FAU - Myllykallio, Hannu
AU  - Myllykallio H
AUID- ORCID: 0000-0002-0541-1197
AD  - Laboratory of Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, 
      Universite Paris Saclay, Palaiseau, France.
FAU - Skouloubris, Stephane
AU  - Skouloubris S
AUID- ORCID: 0000-0001-6660-0023
AD  - Laboratory of Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, 
      Universite Paris Saclay, Palaiseau, France.
AD  - Department of Biology, Universite Paris-Sud, Universite Paris Saclay, Orsay, 
      France.
FAU - Liebl, Ursula
AU  - Liebl U
AUID- ORCID: 0000-0003-0869-4388
AD  - Laboratory of Optics and Biosciences, Ecole polytechnique, CNRS, INSERM, 
      Universite Paris Saclay, Palaiseau, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181214
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Bacterial Proteins)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.1.2.1 (Glycine Hydroxymethyltransferase)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - *Bacterial Proteins/chemistry/genetics/metabolism
MH  - Catalysis
MH  - Escherichia coli/enzymology/genetics
MH  - Folic Acid/chemistry/genetics/metabolism
MH  - Genetic Complementation Test
MH  - Glycine/chemistry/genetics/metabolism
MH  - *Glycine Hydroxymethyltransferase/chemistry/genetics/metabolism
MH  - *Helicobacter pylori/enzymology/genetics
MH  - Protein Domains
PMC - PMC6294363
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/12/15 06:00
MHDA- 2019/05/07 06:00
PMCR- 2018/12/14
CRDT- 2018/12/15 06:00
PHST- 2018/08/23 00:00 [received]
PHST- 2018/11/23 00:00 [accepted]
PHST- 2018/12/15 06:00 [entrez]
PHST- 2018/12/15 06:00 [pubmed]
PHST- 2019/05/07 06:00 [medline]
PHST- 2018/12/14 00:00 [pmc-release]
AID - PONE-D-18-24850 [pii]
AID - 10.1371/journal.pone.0208850 [doi]
PST - epublish
SO  - PLoS One. 2018 Dec 14;13(12):e0208850. doi: 10.1371/journal.pone.0208850. 
      eCollection 2018.